Pharmacokinetic Drug-drug Interaction Study of Dovitinib (TKI258) in Patients With Advanced Solid Tumors. (CTKI258A2120)

A Phase I, Multi-center, Open-label, Drug-drug Interaction Study to Assess the Effect of the CYP1A2 Inhibitor, Fluvoxamine, on Dovitinib (TKI258) Pharmacokinetics in Patients With Advanced Solid Tumors

This is a multi-center, open-label, single-sequence, crossover, drug-drug interaction (DDI) study to assess the effect of the CYP1A2 inhibitor, fluvoxamine, on the PK of dovitinib in patients with advanced solid tumors, excluding breast cancer. The purpose of this study is to evaluate the effect of a CYP1A2 inhibitor, 100 mg fluvoxamine, on the PK of dovitinib when administered at a dose of 300 mg on the dosing schedule, 5 days on/2 days off. The study will consist of 2 phases: a Pharmacokinetic (PK) phase and a clinical treatment phase. The DDI test will be conducted in the PK phase. The DDI test will assess the steady state PK profile of dovitinib when administered alone and in the presence of the CYP1A2 inhibitor, fluvoxamine (AUC 0-24h, AUC 0-72h and Cmax parameters). During the clinical treatment phase patients may continue to receive treatment with TKI258 until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from the study treatment for any other reason.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumors, Excluding Breast Cancer
• Intervention / Treatment: Drug: dovitinib (TKI258); Drug: fluvoxamine

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
• Switzerland
  • Chur, Switzerland, 7000
    • Novartis Investigative Site
  • Genève, Switzerland, 1211
    • Novartis Investigative Site
• United States
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center Montefiore Medical Center (SC)
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy & Research Center / UT Health Science Center SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with a cytopathologically or histopathologically confirmed diagnosis of an advanced solid tumor, excluding breast cancer which has progressed despite standard therapy or for which no standard therapy exists - ECOG performance status 0 or 1 and an anticipated life expectancy of ≥3 months- Patient must meet protocol-specific laboratory values

Exclusion Criteria:

- Patients with brain metastases - Patients who have received or who are expected to receive any prohibited medications and therapies - Patients who have received CYP1A2 or CYP3A inhibitor medications within 5 days prior to start study treatment or are expected to receive during the first 28 days after starting the study treatment - Patients who have received CYP1A2 or CYP3A inducer medications within 30 days prior to start study treatment or are expected to receive during the first 28 days after starting the study treatment - Patients who are actively taking antidepressants, benzodiazepines, serotonergic drugs, and/or monoamine oxidase inhibitors (MAOIs) - Patients who have not recovered from previous anti-cancer therapies - Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258 - Patients who have concurrent severe and/or uncontrolled concomitant medical conditions that could compromise participation in the study - Female patients who are pregnant or breast-feeding - Fertile males or women not willing to use highly effective methods of contraception - Other protocol-defined inclusion/exclusion criteria will apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dovitinib (TKI258); dovitinib, 5 days on / 2 days off dose schedule	Drug: dovitinib (TKI258); Drug: fluvoxamine; perpetrator drug; 7 days of dosing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
TKI258 pharmacokinetics (PK) parameters: Cmax (Maximum (peak) concentration of drug)	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)
TKI258 pharmacokinetics (PK) parameters: AUC 0-24 hr (Area Under the Curve)	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)
TKI258 pharmacokinetics (PK) parameters: AUC 0-72 hr	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)
TKI258 pharmacokinetics (PK) parameters: Tmax (Time to maximum concentration)	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)
TKI258 pharmacokinetics (PK) parameters: T1/2 (Half-life time)	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)
TKI258 pharmacokinetics (PK) parameters: CL/F (Apparent Oral Clearance)	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)
TKI258 pharmacokinetics (PK) parameters: Vz/F (apparent volume of distribution)	multiple time-points over 72h post dose on day Day 19 and Day 26 (PK phase)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and severity of AEs (Adverse Events)		up to at least 30 days after the last dose of dovitinib (TKI258)
Frequency and severity of SAEs (Serious Adverse Events)		up to at least 30 days after the last dose of dovitinib (TKI258)
Preliminary evidence of antitumor activity of dovitinib (TKI258)	overall response based on investigator assessment and best overall response using RECIST 1.1	every 8 weeks until progression of disease

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• de Weger VA, Goel S, von Moos R, Schellens JHM, Mach N, Tan E, Anand S, Scott JW, Lassen U. A drug-drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2018 Jan;81(1):73-80. doi: 10.1007/s00280-017-3469-4. Epub 2017 Nov 3.

Helpful Links

• Results for CTKI258A2120 on the Novartis Clinical Trial Website

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: October 2, 2012
• First Submitted That Met QC Criteria: October 2, 2012
• First Posted (Estimate): October 4, 2012

Study Record Updates

• Last Update Posted (Actual): December 21, 2020
• Last Update Submitted That Met QC Criteria: December 17, 2020
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Anti-Anxiety Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fluvoxamine
• Other Study ID Numbers: CTKI258A2120; 2012-001546-18 (EudraCT Number)